Antiplasmodial\nand Insecticidal Activities of Third-Generation\nIvermectin Hybrids

Preclinical and/or clinical studies have demonstrated\nthe potential\nof Ivermectin (IVM) for malaria control. In order to improve its antiplasmodial\nactivity and build on previous knowledge, we have designed a third\ngeneration of hybrid molecules in which selected pharmacophores were\nappended to the IVM macrolide, while retaining one or both sugar moieties\nat the C-13 position. Moreover, we synthesized IVM hybrids that contain\nstructural features of potent IVM metabolites. The evaluation of the <i>in vitro</i> antiplasmodial activity of these compounds against Plasmodium berghei pre-erythrocytic stages and Plasmodium falciparum erythrocytic stages identified\nmolecules that displayed enhanced activity against the latter when\ncompared to IVM. Additionally, two IVM intermediates and one IVM hybrid\nretained the insecticidal activity of the parental molecule, clarifying\nthe contribution of the sugar moieties to this feature. Altogether,\nthese results provide key structure–activity relationships\nto guide the rational design of new generations of IVM hybrids.